Biomedical subjects

Andrea Hartner

Publications and source records attributed to Andrea Hartner.

At least 19 recordsLinked to original sources

PubMed2006

Renal injury in streptozotocin-diabetic Ren2-transgenic rats is mainly dependent on hypertension, not on diabetes.

Induction of streptozotocin (STZ) diabetes in hypertensive rats transgenic for the mouse ren-2 gene (TGR) has been described as a model of progressive diabetic nephropathy. We investigated the long-term course of STZ diabetes in TGR and appropriate Sprague-Dawley control rats (SD) and tested the role of angiotensin-dependent hypertension by treating rats with the angiotensin II type 1 receptor blocker losartan (1 mg.kg(-1).day(-1)) via osmotic minipumps. Five weeks after STZ injection, diabetes developed in TGR and SD. Urinary albumin excretion was increased by diabetes and, to a much higher degree, by hypertension. The effects of hypertension and diabetes were not additive, and only the effects of hypertension were ameliorated by losartan. A similar pattern was observed for cell proliferation and macrophage infiltration in the kidney. In contrast, the effects of hypertension and diabetes on glomerular collagen IV accumulation were additive 5 wk after STZ injection. In a long-term study for 20 wk after STZ, survival was better in STZ-treated TGR than in normoglycemic TGR, whereas all SD survived. Impaired creatinine clearance and increased macrophage infiltration as well as glomerular and interstitial matrix deposition were prominent in TGR compared with SD, regardless of the presence or absence of diabetes. In conclusion, STZ diabetes in TGR may be useful to study glomerular and interstitial matrix deposition early in the course of diabetes. However, the long-term course of this animal model resembles severe hypertensive nephrosclerosis, rather than progressive diabetic nephropathy.

Albuminuria↗

PubMed2006

Angiotensin II formation in the kidney and nephrosclerosis in Ren-2 hypertensive rats.

BACKGROUND: Ren-2 transgenic hypertensive rats develop malignant hypertensive nephrosclerosis despite low to normal plasma angiotensin II and suppressed renal renin. We tested the hypothesis that local angiotensin II formation occurs at sites of renal vascular and interstitial injury in this model. METHODS: Heterozygous Ren-2 transgenic rats were compared with normotensive Sprague-Dawley-Hannover control rats and Ren-2 transgenic rats treated with a very low dose of an angiotensin II type 1 (AT1) receptor antagonist, 1 mg/kg/day losartan, for 4 weeks. Blood pressure measurements, quantifications of urinary albumin, plasma and tissue angiotensin II as well as immunohistochemical analyses were performed. RESULTS: Systolic blood pressure was not affected by losartan during the study but intra-arterial recordings revealed a decrease of blood pressure. Losartan reduced albumin excretion, cell proliferation, macrophage influx, collagen I and collagen IV deposition. Plasma angiotensin II was decreased, while kidney tissue angiotensin II content was increased in Ren-2 transgenic rats compared with control rats. In Ren-2 transgenic rats, juxtaglomerular renin and angiotensin II staining were reduced, but there was a marked angiotensin II staining at foci of tubulo-interstitial fibrosis and at proliferative malignant vascular lesions. CONCLUSION: We conclude that local angiotensin II formation is increased in proliferative or fibrotic kidney lesions in the Ren-2 transgenic rat. Local angiotensin II formation may help to explain why the AT1 receptor antagonist prevents or ameliorates this transgenic model of malignant nephrosclerosis despite low to normal plasma angiotensin II and suppressed renal renin.

Angiotensin II↗

PubMed2005

Role of fibrillin-1 in hypertensive and diabetic glomerular disease.

The microfibrillar protein fibrillin-1 is a component of the mesangial matrix. Defects in fibrillin-1 predisposes individuals to vascular damage in Marfan syndrome, but the role of fibrillin-1 in kidney disease is unknown. We hypothesized that fibrillin-1 is involved in hypertensive or diabetic glomerular disease. DOCA-salt hypertension or streptozotocin (STZ) diabetes led to a significant increase in glomerular fibrillin-1 deposition. To test the functional role of fibrillin-1, DOCA hypertension and STZ diabetes were induced in mice homozygous for a mutation leading to a fivefold lower expression of fibrillin-1 (mgR/mgR). Untreated male mgR/mgR mice usually die from aortic dissection during the first 4 mo of life. All DOCA-treated mgR/mgR mice died within 2 wk after onset of DOCA treatment. DOCA-treated heterozygous (mgR/+) and their wild-type littermates displayed similar blood pressure levels, but albuminuria was significantly lower in mgR/+ than in wild-type mice after DOCA treatment. Similarly, STZ diabetic mgR/mgR and mgR/+ developed lower albuminuria than wild-type mice despite higher blood glucose levels in mgR/mgR and mgR/+ compared with wild-type mice. Blood pressure, blood glucose, and albuminuria did not differ among untreated mgR/mgR, mgR/+, and wild-type mice, respectively. In diabetic mgR/+ and mgR/mgR, but not in wild-type mice, an induction of glomerular decorin expression was observed. Thus underexpression of fibrillin-1 predisposes individuals to lethal aortic dissection in the presence of hypertension. On the other hand, albuminuria as a parameter of microvascular damage in hypertension and diabetes was ameliorated in fibrillin-1-underexpressing mice, possibly due to a compensatory upregulation of decorin. We conclude that fibrillin-1 may contribute to glomerular damage in hypertensive and diabetic kidney disease.

Albuminuria↗

PubMed2005

Induction and coexpression of latent transforming growth factor beta-binding protein-1 and fibrillin-1 in experimental glomerulonephritis.

BACKGROUND: Latent transforming growth factor-beta-binding protein 1 (LTBP-1) and fibrillin-1 were shown to colocalize and interact in the extracellular matrix of the skin and vasculature. This interaction may regulate transforming growth factor-beta (TGF-beta) activity. TGF-beta is an important progression factor for glomerular diseases. We hypothesized that LTBP-1 and fibrillin-1 are coexpressed in the glomerulus and upregulated during glomerulonephritis. METHODS: Acute anti-Thy1.1 glomerulonephritis was induced with a single intravenous injection (1 mg/kg body weight) of a monoclonal anti-Thy1.1 antibody in rats. Real-time RT-PCR and immunohistochemical analyses for LTBP-1 and fibrillin-1 were performed. RESULTS: Induction of glomerular LTBP-1 mRNA was detected on day 2 of disease, while mRNA for fibrillin-1 was already upregulated 1 day after induction of disease. Both LTBP-1 and fibrillin-1 showed a mesangial distribution. An expansion of the LTBP-1 and fibrillin-1-positive mesangial area was seen on day 6 of disease, when transient matrix accumulation was most prominent. On day 12 of disease, glomerular LTBP-1 and fibrillin-1 immunoreactivities had returned to control levels. In serial sections, some colocalization of LTBP-1 and fibrillin-1 was detected in control as well as in nephritic glomeruli. CONCLUSION: Mesangial expression of LTBP-1 and fibrillin-1 is induced early in experimental nephritis and LTBP-1 and fibrillin-1 are partially colocalized in the nephritic glomerulus. An interaction of these molecules could stabilize latent TGF-beta complexes and thus attenuate the activation of TGF-beta during this self-limited glomerular disease.

Animals↗

PubMed2005

Effects of diabetes and hypertension on macrophage infiltration and matrix expansion in the rat kidney.

BACKGROUND: In experimental models of diabetes mellitus, aggravation of renal injury by concomitant hypertension has been described. Inflammatory mechanisms contribute to renal damage in both diseases. We investigated whether hypertension and diabetes mellitus act synergistically to induce macrophage infiltration and matrix expansion in the kidney. METHODS: Insulin-dependent diabetes mellitus was induced by streptozotocin injections to hypertensive mRen2-transgenic rats (TGR) and normotensive Sprague-Dawley control rats. Quantitative immunohistochemical examination of kidney tissue sections was used to measure macrophage infiltration and matrix expansion. The expression of MCP-1, Osteopontin, RANTES, ICAM-1 and VCAM-1 was evaluated by real-time RT-PCR. The localization of MCP-1 was studied by immunohistochemistry. RESULTS: Macrophage infiltration was present in the kidney of normotensive diabetic rats. Hypertensive rats exhibited a more marked infiltration of macrophages, regardless of whether diabetes was present or not. Gene expression of ICAM-1, VCAM-1 and RANTES was unaltered whereas Osteopontin and MCP-1 were induced by hypertension. Immunoreactive MCP-1 was slightly increased in diabetic rat kidney podocytes, and more markedly increased in hypertensive animals. Glomerular matrix accumulation was induced by diabetes and hypertension to a similar degree, and was highest in hypertensive, diabetic animals. CONCLUSION: Diabetes mellitus caused a mild, and angiotensin-dependent hypertension a more marked infiltration of macrophages in the kidney. Combination of both diseases led to additive effects on matrix expansion but not on inflammation. Hypertension appears to be a much stronger stimulus for inflammation of the kidney than STZ diabetes, at least in mRen2-transgenic rats.

Animals↗

PubMed2005

Effects of sympathetic nerves and angiotensin II on renal sodium and water handling in rats with common bile duct ligature.

We tested the hypothesis that angiotensin II is likely to be mandatory for the neurogenic sodium and volume retention in cirrhotic rats with common bile duct ligature (BDL) following an acute volume load. To assess the neural control of volume homeostasis, 21 days after common BDL rats underwent volume expansion (0.9% NaCL; 10% body wt over 30 min) to decrease renal sympathetic nerve activity. Untreated animals, rats with renal denervation or pretreated with a nonhypotensive dose of an angiotensin II type 1 receptor antagonist were studied. The renal renin-angiotensin system was assessed by immunohistochemistry and RT-PCR. Rats with BDL excreted only 71 +/- 4% of the administered volume load. In cirrhotic rats pretreated with an angiotensin II AT1 inhibitor or after renal denervation, these values ranged significantly higher from 98 to 103% (P < 0.05 for all comparisons). Renal sympathetic nerve activity decreases by volume expansion were impaired in BDL rats (P < 0.05) but unaffected by angiotensin II receptor inhibition. In kidneys of BDL animals, renin mRNA was increased, and immunohistochemistry revealed increased staining for peritubular angiotensin II. Renal denervation in BDL animals reduced renin expression within 5 days to control levels. In conclusion, the impaired excretion of an acute volume load in rats with liver cirrhosis is due to effects of an increased renal sympathetic nerve activity that are likely to be dependent on intrarenal angiotensin II and renin. We speculate that similar changes may contribute to long-term volume retention in liver cirrhosis.

Angiotensin II↗

PubMed2005

Adrenomedullin reduces mesangial cell number and glomerular inflammation in experimental mesangioproliferative glomerulonephritis.

BACKGROUND: Adrenomedullin (ADM) is a vasodilator peptide that is abundantly expressed in the kidney. ADM has antiproliferative effects on glomerular mesangial cells (MC) in vitro. Whether or not treatment with ADM can reduce MC proliferation in vivo [i.e., in mesangioproliferative glomerulonephritis (GN)] is unknown. We tested the hypothesis that ADM substitution reduces MC proliferation in GN. METHODS: GN in rats was induced by injection of an anti-Thy-1.1 antibody. Rats received osmotic minipumps, which continuously delivered rat ADM (500 ng/hour, N = 11), or vehicle (N = 13) from day 3 to day 6 after GN induction. Rats were sacrificed 6 days after induction of GN. On kidney sections, cells staining positive for proliferating cell nuclear antigen, mesangial cells, monocytes, and apoptotic cells were counted. Parameters of inflammation and fibrosis were measured in renal cortex and sieved glomeruli by real-time polymerase chain reaction (PCR). RESULTS: Systolic blood pressure, diuresis, albuminuria, creatinine clearance, microaneurysm formation, and mesangial matrix expansion were not influenced by ADM infusion. However, ADM treatment significantly reduced the number of MC, showed a tendency to reduce total glomerular cell proliferation, and significantly increased apoptosis. ADM-treated GN animals showed significantly less glomerular monocyte infiltration. ADM treatment normalized transforming growth factor (TGF)-beta1 mRNA expression and reduced monocyte chemoattractant protein-1 (MCP-1), osteopontin, plasminogen activator inhibitor-1 (PAI-1), collagen I, and collagen III mRNA expression significantly. CONCLUSION: Exogenous ADM infusion reduces MC number and glomerular monocyte infiltration in the state of mesangial proliferation during acute experimental mesangioproliferative GN. These findings indicate that ADM can influence the course of mesangioproliferative GN.

Adrenomedullin↗

PubMed2004

Characterization of the renal phenotype in a mouse model of Marfan syndrome.

The microfibrillar protein fibrillin-1 is expressed abundantly in the vasculature and the glomerulus of the kidney. Mutations in the fibrillin-1 gene lead to Marfan syndrome. The most common complication of this disease is aortic dilatation due to elastic deficiencies of the vascular wall. Several case reports describe glomerular disease in patients with Marfan syndrome, and fibrillin-1 has been implicated in nephrogenesis. To study the role of fibrillin-1 in renal development and function, we characterized the renal phenotype of fibrillin-1-underexpressing mice. Kidney histology was evaluated by means of morphometry and stereology. Relative kidney weights, daily urine excretion, urinary albumin excretion, serum and urinary creatinine, as well as serum urea were not different than wild-type mice. Glomerular number and renal capillarization were normal. The size of the renal filtration surface was comparable in wild-type and fibrillin-1-underexpressing mice. There was no indication for glomerular, renal vascular, or tubulointerstitial injury. However, glomerular volume and mesangial area were reduced. No changes in glomerular cell numbers were detected, but the cellular volume of mesangial cells was significantly lower in glomeruli of fibrillin-1-underexpressing mice. Thus, despite the high abundance of fibrillin-1 in glomeruli of wild-type animals, underexpression of fibrillin-1 did not lead to functional deficiencies of the glomerulus. Alterations in renal histology were only subtle with a reduced glomerular volume and mesangial area likely due to a reduced mesangial cell volume.

Animals↗

PubMed2003

Differential regulation of osteopontin expression in the clipped and nonclipped kidney of two-kidney, one-clip hypertensive rats.

BACKGROUND: Osteopontin (Opn) is highly upregulated in many different animal models of renal disease, where it is suspected to participate in progression of the disease. In some models, angiotensin II (Ang II) seems to induce the elevated Opn production. Therefore, we examined the regulation of Opn in two-kidney, one-clip (2K1C) hypertensive rats, in which Ang II mediates the elevated blood pressure. METHODS: At days 7, 14, and 28, the clipped and nonclipped kidneys of hypertensive or sham-operated rats were analyzed for osteopontin protein, mRNA expression and mononuclear cell infiltration by imumunohistochemistry, in situ hybridization, and Northern blot analysis. Rats were treated with the Ang II type 1 receptor antagonist Valsartan starting 14 days after clipping. RESULTS: In sham-operated rats, Opn was mainly localized to cells of the thin ascending limbs of the outer medulla. No significant Opn staining was observed in cortical tubules. Focally defined tubular cortical Opn staining was observed in clipped and contralateral kidneys of hypertensive animals at days 14 and 28. Osteopontin protein expression correlated with the mRNA expression detected by in situ hybridization and Northern blot. Treatment with Valsartan reduced osteopontin staining by 51%, mRNA by 47%, and mononuclear cell number by 97% in nonclipped kidneys compared to untreated two-kidney, one-clip animals. In clipped kidneys, however, Opn protein and mRNA expression was not reduced, but a 240% increase in interstitial mononuclear cell number was observed. CONCLUSIONS: Osteopontin is involved in the induction of nephrosclerosis in renovascular hypertension, probably by a mechanism augmenting monocyte infiltration. Angiotensin II appears to be an important inducer of Opn in the nonclipped kidney. Ischemic conditions may regulate Opn expression in the clipped kidney.

Angiotensin Receptor Antagonists↗

PubMed2003

Role of alpha8 integrin in mesangial cell adhesion, migration, and proliferation.

BACKGROUND: Extracellular matrix receptors of the integrin family are known to regulate cell adhesion, migration, and proliferation. The alpha8 integrin chain is expressed in the glomerulus exclusively by mesangial cells. The contribution of alpha8 to mesangial cell function, however, has not yet been studied. METHODS: Mesangial cells from wild-type and alpha8-deficient mice were isolated and characterized. Integrin expression was assessed by real-time polymerase chain reaction (PCR), Western blot, or fluorescence-activated cell sorter (FACS) analysis. Cell adhesion was determined by conventional attachment assay and a centrifugal assay for cell adhesion. Cell migration was determined by a fluorescence-based transmigration assay and a chemotaxis assay. Proliferation rates were determined by BrdU and [3H]-thymidine assays. RESULTS: On the alpha8 ligands fibronectin and vitronectin, but not on collagens, attachment of alpha8-deficient mesangial cells was reduced compared to wild-type cells. In contrast, alpha8-deficient mesangial cells migrated more easily and displayed an increased proliferative response on fibronectin or vitronectin, but not on collagens, compared to wild-type cells. These effects were not due to an up-regulation of the fibronectin or vitronectin receptors alpha5 or alphav in alpha8-deficient mesangial cells, as the cell surface expression of integrins alpha5 and alphav was comparable in wild-type and alpha8-deficient mesangial cells. CONCLUSION: These findings confirm a role for alpha8 integrin in the regulation of the mesangial cell phenotype. alpha8 integrin seems to promote adhesion, but inhibit migration and proliferation of mesangial cells. Thus, the data support the hypothesis that alpha8 integrin could play an important role for maintaining tissue integrity in the glomerulus during glomerular injury.

Animals↗

PubMed2003

Strain differences in the development of hypertension and glomerular lesions induced by deoxycorticosterone acetate salt in mice.

BACKGROUND: The genetic background may exert important modifying effects on the course and severity of experimental kidney diseases in mice. We investigated its influence on the development of hypertension and renal injury following treatment with deoxycorticosterone acetate (DOCA) salt in several mouse strains. METHODS: Four mouse strains were used for comparison: 129/Sv, C57BL/6 and F1 and F2 intercrosses of 129/Sv x C57BL/6. Male mice were uninephrectomized and DOCA hypertension was induced for 6 weeks. DOCA animals and controls received 1% NaCl for drinking. Renal damage was evaluated following measurements of blood pressure, urine albumin and renal matrix expansion. RESULTS: DOCA-induced blood pressure increase, glomerulosclerosis, interstitial fibrosis and albuminuria were markedly higher in 129/Sv than in C57BL/6 mice. F1 and F2 intercrosses displayed intermediate blood pressure, glomerular and interstitial fibrosis comparable to C57BL/6 but albuminuria as high as 129/Sv mice. CONCLUSIONS: 129/Sv mice are more susceptible to the development of DOCA-induced high blood pressure and renal damage than C57BL/6 mice. Intercrosses of both strains show a complex and non-uniform segregation of the susceptibility to DOCA-salt hypertension and nephrosclerosis.

Analysis of Variance↗

PubMed2003

Glomerular and renal vascular structural changes in alpha8 integrin-deficient mice.

Integrins are matrix receptors that regulate cell-matrix interactions during development and in adult tissue. In the adult kidney, the alpha8 chain is specifically expressed in glomerular mesangial cells and vascular smooth muscle cells. alpha8-deficient (alpha8-/-) mice demonstrate reductions in renal mass, which can range from complete renal agenesis to the development of kidneys that are only slightly smaller than wild-type kidneys. No histologic abnormalities of these kidneys have been described. However, considering the prominent expression of alpha8 in glomeruli and renal vessels, it seemed unlikely that the kidneys of alpha8-/- mice would be completely normal. Therefore, the renal phenotype of adult alpha8-/- mice was investigated, for assessment of more subtle morphologic alterations in kidney tissue. alpha8-/- mice displayed a significant reduction in nephron number and an increase in glomerular volume, compared with wild-type control animals. Albuminuria was not different in wild-type and alpha8-/- mice. Quantitative morphologic analyses revealed that the glomeruli of alpha8-/- mice were hypercellular, with an increased number of mesangial cells, compared with wild-type mice. Mesangial matrix deposition (as demonstrated for collagen IV and the alpha8 ligand fibronectin) was expanded in alpha8-/- mice, compared with wild-type mice. Collagens I and III, which are not normally present in glomeruli, were detected in the glomeruli of alpha8-/- mice. Staining for other glomerular integrins demonstrated an increased abundance of the collagen receptor alpha2 integrin in alpha8-/- mice. The glomerular capillary length density was significantly greater in alpha8-/- mice than in wild-type mice. Cortical arterial vessel walls were not altered in alpha8-/- mice, but the capillaries of the peritubular network were widened. Despite the strong mesangial and vascular expression of alpha8, glomerular and renal vascular alterations in alpha8-/- mice were relatively mild. Only aged alpha8-/- mice demonstrated increased glomerular capillary widening, compared with control animals. The results suggest that the lack of alpha8 can be largely compensated for, at least in younger alpha8-/- mice. It is not yet clear whether the occurrence of collagens that are not normally present in glomeruli and the increased abundance of the collagen receptor alpha2 contribute to maintaining the glomerular structure in alpha8-/- mice. The compensatory mechanisms involved will be the subject of future research.

Animals↗

PubMed2002

Dynamic expression patterns of transforming growth factor-beta(2) and transforming growth factor-beta receptors in experimental glomerulonephritis.

Numerous studies have demonstrated the involvement of the transforming growth factor (TGF) isoform beta(1) in the pathogenesis of renal fibroproliferative diseases. Although in vitro studies suggest that TGF-beta(2) is equally potent to TGF-beta(1) in terms of its antimitogenic and fibrogenic effects, much less is known about the regulation of TGF-beta(2) in renal diseases associated with glomerular cell hyperplasia and matrix expansion. Here we investigated the glomerular expression patterns of TGF-beta(2) and of the TGF-beta receptors I, II, and III during the course of rat anti-Thy1.1 nephritis (days 2, 6, 12, and 56), a model characterized by transient mesangial hypercellularity and extracellular matrix accumulation. TGF-beta(2) exhibited dynamic changes in expression. Immunohistochemical double-staining of renal sections revealed that most TGF-beta(2)-positive cells in control glomeruli were podocytes with few TGF-beta(2)-positive mesangial cells. This staining pattern could also be observed in human kidney. On day 6 of anti-Thy1.1 nephritis both TGF-beta(2) positive podocytes and mesangial cells were more abundant. By western blot analysis of isolated glomeruli from nephritic rats, protein expression of TGF-beta(2) was upregulated tenfold over control glomeruli, peaking on day 6 of the disease. In cultured rat mesangial cells we found that the TGF-beta(2) and TGF-beta(1) isoforms were equally potent in terms of nuclear accumulation of phosphorylated Smad 2/3, inhibition of DNA synthesis, and induction of beta(1)-integrin and type I collagen protein synthesis. Protein expression of the TGF-beta receptor I was not detected by immunohistochemistry in control glomeruli but was markedly induced in the mesangium on day 6 of nephritis. Mesangial staining for TGF-beta receptors II and III was detected in normal kidneys. Expression of TGF-beta receptor II was strongly enhanced on days 6 and 12 of disease, while TGF-beta receptor III was upregulated only on day 6. In summary, we report marked yet transient upregulation of TGF-beta(2) protein and of TGF-beta receptors I, II, and III in glomerular cells during anti-Thy1.1 nephritis. These results are in keeping with the notion that TGF-beta(2) and its receptors participate in the pathogenesis and/or resolution of this transient form of glomerulonephritis.

Animals↗

PubMed2002

Role of macula densa cyclooxygenase-2 in renovascular hypertension.

Upregulation of the inducible cyclooxygenase (COX-2) in the macula densa accompanies the activation of the juxtaglomerular apparatus in many high-renin conditions. The functional role of COX-2 in these disease states is poorly understood. We tested whether COX-2 is required to increase renin in renovascular hypertension. Rats with established two-kidney, one-clip (2K1C) hypertension were treated for 2 wk with two different inhibitors of COX-2, NS-398 and rofecoxib, respectively. Hypertension in 2K1C rats was not affected or slightly enhanced by COX-2 inhibition, as measured intra-arterially in conscious animals. The increase in plasma renin activity was also unchanged by both rofecoxib and NS-398. The number of glomeruli with a renin-positive juxtaglomerular apparatus was elevated in clipped kidneys and decreased in contralateral kidneys of 2K1C rats. This pattern was unaltered by COX-2 inhibition. To test the effects of COX-2 blockade on a primarily macula densa-mediated stimulus, we studied salt depletion for comparison. A low-salt diet induced a significant increase in plasma renin activity, which was partially inhibited by treatment with NS-398. We conclude that inhibition of COX-2 in established renovascular hypertension does not affect renin synthesis or release. Thus either COX-2 is not necessary for the macula densa mechanism or the macula densa is not important for maintaining high renin in renovascular hypertension.

Animals↗

PubMed2002

Lessons in congenital and acquired renal disease from alpha8 integrin mutant mice.

Cell-matrix interactions have been shown to be important during renal development and in various forms of kidney diseases. The alpha8 integrin chain is expressed during early nephrogenesis. In alpha8 gene mutated mice, lack of alpha8 results in unilateral or bilateral renal agenesis in part of the animals. No human disease with mutations in the alpha8 integrin gene locus has been described to date. However, similar renal defects are displayed in disorders with mutations affecting other adhesion molecules. In the kidneys of adult mice, alpha8 is expressed in vascular smooth muscle cells and mesangial cells of the glomerulus. Although alpha8-deficient mice surviving with reduced renal mass do not show any glomerular abnormalities, they have an increased susceptibility to glomerular damage upon mechanical or inflammatory stress of glomerular cells. Thus, alpha8 seems to be important for normal renal development and could help to maintain the structural integrity of the glomerulus following injury during various kidney diseases.

Animals↗

PubMed2002

The alpha8 integrin chain affords mechanical stability to the glomerular capillary tuft in hypertensive glomerular disease.

In the kidney, the alpha8 integrin chain is expressed in glomerular mesangial cells. The alpha8 integrin plays a role in early nephrogenesis but its functional role in the adult kidney is unknown. We tested the hypothesis that alpha8 integrin-mediated cell-matrix interactions are important to maintain the integrity of the glomerulus in arterial hypertension. Desoxycorticosterone (DOCA)-salt hypertension was induced in mice homozygous for a deletion of the alpha8 integrin chain and wild-type mice. Blood pressure, albumin excretion, total renal mass, and glomerular filtration in DOCA-treated alpha8-deficient mice were comparable to DOCA-treated wild types. DOCA-treated wild types showed increased glomerular immunostaining for alpha8 integrin compared to salt-loaded and untreated controls, whereas the glomeruli of alpha8-deficient mice always stained negative. Morphometric studies revealed similar degrees of glomerulosclerosis in DOCA-treated alpha8-deficient and DOCA-treated wild-type mice. However, DOCA-treated alpha8-deficient mice had a higher score of capillary widening (mesangiolysis) than DOCA-treated wild-type mice, which was confirmed in two additional wild-type strains. Moreover, in DOCA-treated alpha8-deficient mice, glomerular fibrin deposits were more frequent than in DOCA-treated wild types. The results show that lack of alpha8 is associated with increased susceptibility to glomerular capillary destruction in DOCA salt hypertension, whereas it does not seem to play a major role in the development of fibrosis or glomerulosclerosis. Our findings indicate that mesangial alpha8 integrin contributes to maintain the integrity of the glomerular capillary tuft during mechanical stress, eg, in hypertension.

Animals↗

PubMed2002

Aspects of the renal phenotype of adult alpha8 integrin-deficient mice.

Integrins mediate cell-matrix interactions which are important for organ development. In the kidney, alpha8 integrin is expressed during early nephrogenesis. In alpha8 gene-mutated mice, lack of alpha8 leads to unilateral or bilateral renal agenesis in part of the animals. We investigated surviving animals with one or two kidneys. These mice had significantly reduced renal mass and displayed higher blood pressure compared with the wild-type. Furthermore, most of them revealed urine concentration defects. Many alpha8-deficient mice also exhibited segmental malformations of the kidney with collapse or atrophy of tubuli and interstitial cell infiltrates. These data provide further evidence that alpha8 has important functions in renal development.

Animals↗

PubMed2000

Nitric oxide synthase isoforms and glomerular hyperfiltration in early diabetic nephropathy.

This study tested the hypothesis that nitric oxide (NO)-mediated renal vasodilation due to the activity of the inducible nitric oxide synthase (iNOS) contributes to glomerular hyperfiltration in diabetic rats. Two weeks after induction of diabetes mellitus by streptozotocin, mean arterial BP (MAP), GFR (inulin clearance), and renal plasma flow (RPF) (para-aminohippurate clearance) were measured in conscious instrumented rats. Diabetic rats had elevated GFR (3129 +/- 309 microl/min versus 2297 +/- 264 microl/min in untreated control rats, P < 0.05) and RPF (10526 +/- 679 microl/min versus 8005 +/- 534 microl/min), which was prevented by chronic insulin treatment. Intravenous administration of 0.1 and 1 mg of L-imino-ethyl-lysine (L-NIL), an inhibitor of iNOS, did not affect MAP, GFR, or RPF, either in diabetic or control rats. A higher L-NIL dose (10 mg) increased MAP and decreased RPF in diabetic rats significantly (n = 6, P < 0.05), but not in controls (n = 6). In addition, 0.1 mg of NG-nitro-L-arginine methyl ester (L-NAME), a nonselective blocker of NOS isoforms, decreased GFR (2389 +/- 478 microl/min) and RPF (7691 +/- 402 microl/min) in diabetic animals to control levels, while renal hemodynamics in normoglycemic rats were not altered. Higher L-NAME doses (1 and 10 mg) reduced GFR and RPF in diabetic and control rats to identical levels. In glomeruli isolated from diabetic and control rats, neither iNOS mRNA nor iNOS protein expression was detected. In contrast, increased protein levels of endothelial constitutive NOS (ecNOS) were found in glomeruli of diabetic rats compared with controls. By immunohistochemistry, ecNOS but not iNOS staining was observed in the endothelium of preglomerular vessels and in diabetic glomeruli. These results support the notion that increased NO availability due to greater abundance of ecNOS contributes to the pathogenesis of glomerular hyperfiltration in early experimental diabetic nephropathy. In contrast, we found no functional or molecular evidence for increased glomerular expression and activity of iNOS in diabetic rats.

Animals↗